This research program (GM-41821), now in its seventh year, embodies our long-term commitment to the design and synthesis on non-peptide peptidominetics. The principal goals for years 8 through 11 are: (A) In the SRIF receptor project we will continue to optimize the sugar scaffold and the side chains, to produce ligands with both nanomolar and subnanomolar affinities especially for the receptor subtype 2 (SSTR 2) and good pharmacokinetic properties. These efforts will build on advances with: (1) mannose-based immidazole sugars; (2) desindole sugars; (3) unsaturated lysine-containing sugars; and further explore (4) modifications of the indole side chain; and (5) incorporation of fromamidines. In addition, we will: (6) seek to understand the factors responsible for SSTR specificity; and (7) continue to test for SRIF antagonism. (B) In our NK-1 receptor program we will: (1) define the binding mode of sugar-based ligands to the NK-1 receptor; (2) use the c-hexapeptide 17 to design a sugar ligand; (3) improve the solubility of our mimetics by introducing glucosamine-based sugars and replacing benzyl side-chains with pyridyl analogs; (4) employ 17 as a template for conversion of the tetradecapeptide hormone somatostatin (SRIF) into an NK-1 receptor. (C) To close the loop between the peptide and non-peptide ligands for G-protein-coupled receptors, will return to the beta2-adrenergic receptor and: (1) attempt to design the first peptidal ligand by mimicking the structures of our polyvalent sugars; (2) use the latter results to optimize the sugar lead; and (3) test these compounds for Beta 3-adrenergic receptor affinity. (D) Exploiting the fact that the cyclic hexapeptide scaffold represents a privileged platform, we will also: (1) optimize the first non-amine-containing peptidal morphine receptor ligands, which we discovered; and (2) design an opiate sugar, once again based upon the corresponding peptide data. (E) As one approach to increasing diversity, we propose to construct novel privileged platforms by preparing chimeric sugars integrated into: (1) the benzodiazepine framework and (2) the so-called tricyclic platform. We will submit the resulting compounds to broad-based receptor screening at DuPont Merck, Merck Research Laboratories, and possibly elsewhere. (F) Because our sugars represent a new class of privileged platforms, we will generate small libraries of monosaccharides via parallel solid-phase synthesis (SPS).